The present invention relates to pharmaceutical agents which are xcex1Vxcex23 and/or xcex1Vxcex25 integrin antagonists and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by xcex1Vxcex23 and/or xcex1Vxcex25 integrins.
Integrins are a group of cell surface glycoproteins which mediate cell adhesion and therefore are useful mediators of cell adhesion interactions which occur during various biological processes. Integrins are heterodimers composed of noncovalently linked xcex1 and xcex2 polypeptide subunits. Currently eleven different xcex1 subunits have been identified and six different xcex2 subunits have been identified. The various xcex1 subunits can combine with various xcex2 subunits to form distinct integrins.
The integrin identified as xcex1Vxcex23 (also known as the vitronectin receptor) has been identified as an integrin which plays a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis (Ross, et al., J. Biol, Chem., 1987, 262, 7703), Paget""s disease, humoral hypercalcemia of malignancy (Carron et al., Cancer Res. 1998, 58, 1930), osteopenia (Lark et al., J Bone Miner Res. 2001, 16, 319), endometriosis (Healy et al., Hum. Reproductive Update, 1998, 4, 736), angiogenesis, including tumor angiogenesis (Cheresh, Cancer Metastasis Rev., 1991, 10, 3-10 and Brooks, et al., Cell, 1994, 79, 1157), retinopathy including macular degeneration (Friedlander et al., Proc. Natl. Acad. Sci USA 1996, 93, 9764), arthritis, including rheumatoid arthritis (Badger et al., Arthritis Rheum, 2001, 44, 128), periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis and artherosclerosis, (Brown et al., Cardiovascular Res., 1994, 28, 1815). The compounds of the present invention are xcex1Vxcex23 antagonists and can be used, alone or in combination with other therapeutic agents, in the treatment or modulation of various conditions or disease states described above. Additionally, it has been found that such agents would be useful as antivirals, antifungals and antimicrobials. Thus, compounds which selectively antagonize xcex1Vxcex23 would be beneficial for treating such conditions.
The integrin xcex1Vxcex25 plays a role in neovascularization. Antagonists of the xcex1Vxcex25 integrin will inhibit neovascularization and will be useful for treating and preventing angiogenesis metastasis, tumor growth, macular degeneration and diabetic retionopathy. M. C. Friedlander, et al., Science, 270, 1500-1502 (1995) disclose that a monoclonal antibody for xcex1Vxcex25 inhibits VEFG-induced angogenesis in the rabbit cornea and the chick chorioallantoic membrane model. Therefore, it would be useful to antagonize both the xcex1Vxcex25 and the xcex1Vxcex23 receptor. Such xe2x80x9cmixed xcex1Vxcex25/xcex1Vxcex23 antagonistsxe2x80x9d or xe2x80x9cdual xcex1Vxcex23/xcex1Vxcex25 antagonistsxe2x80x9d would be useful for treating or preventing angiogenesis, tumor metastasis, tumor growth, diabetic retinopathy, macular degeneration, atherosclerosis and osteoporosis.
It has been shown that the xcex1Vxcex23 integrin and other xcex1V containing integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules. Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors. However, it is also known that RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides which bind to xcex1Vxcex23 also bind to xcex1Vxcex25, xcex1Vxcex21 and xcex1IIbxcex23. Antagonism of platelet xcex1IIbxcex23 (also known as the fibrinogen receptor) is known to block platelet aggregation in humans. In order to avoid bleeding side-effects when treating the conditions or disease states associated with the integrin xcex1Vxcex23, it would be beneficial to develop compounds which are selective antagonists of xcex1Vxcex23 as opposed to xcex1IIbxcex23.
Further, it has not been established in the art that sparing xcex1Vxcex26 integrin would be a beneficial property to be incorporated in the design of antagonists of xcex1Vxcex23. Rather, xcex1Vxcex26 has been identified as a target for antagonists because it is higly expressed in many carcinoma cell lines, and has been shown to enchance the proliferative capacity of a colon carcinoma cell line both in vivo and in vitro (Agrez et al., 1994, J. Cell Biol. 127, 547). Additionally, xcex1Vxcex26 is expressed during the later stages of wound healing and remains expressed until the wound is closed (See Christofidou-Solomidou, et al., 1997 American J. of Pathol., 151, 975), and therefore it is believed that xcex1Vxcex26 plays a role in the remodeling of the vasculature during the later stages of angiogenesis. Accordingly, antagonists of xcex1Vxcex26 are seen as useful in treating or preventing cancer by inhibiting tumor growth and metastasis (see, for example, U.S. Pat. No. 6,211,191).
Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic dissolution of the matrix; and 3) movement of the cells through the dissolved barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor.
Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992) 1557-1561) have shown that the xcex1Vxcex23 integrin has a biological function in melanoma cell invasion. Montgomery et al., (Proc. Natl. Acad. Sci. USA, Vol. 91 (1994) 8856-60) have demonstrated that the integrin xcex1Vxcex23 expressed on human melanoma cells promotes a survival signal, protecting the cells from apoptosis. Mediation of the tumor cell metastatic pathway by interference with the xcex1Vxcex23 integrin cell adhesion receptor to impede tumor metastasis would be beneficial.
Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstrated that antagonists of xcex1Vxcex23 provide a therapeutic approach for the treatment of neoplasia (inhibition of solid tumor growth) since systemic administration of xcex1Vxcex23 antagonists causes dramatic regression of various histologically distinct human tumors.
The adhesion receptor integrin xcex1Vxcex23 was identified as a marker of angiogenic blood vessels in chick and man and therefore such receptor plays a critical role in angiogenesis or neovascularization. Angiogenesis is characterized by the invasion, migration and proliferation of smooth muscle and endothelial cells. Antagonists of xcex1Vxcex23 inhibit this process by selectively promoting apoptosis of cells in neovasculature. The growth of new blood vessels, or angiogenesis, also contributes to pathological conditions such as diabetic retinopathy including macular degeneration (Adamis et al., Amer. J. Ophthal., Vol. 118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp. Med., Vol. 175, (1992), 1135-1138). Therefore, xcex1Vxcex23 antagonists would be useful therapeutic agents for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571).
It has been reported that the cell surface receptor xcex1Vxcex23 is the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption and when such bone resorbing activity exceeds bone forming activity it results in osteoporosis (loss of bone), which leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of xcex1Vxcex23 have been shown to be potent inhibitors of osteoclastic activity both in vitro [Sato et al., J. Cell. Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et al., Endocrinology, Vol. 132 (1993) 1411-1413]. Antagonism of xcex1Vxcex23 leads to decreased bone resorption and therefore restores a normal balance of bone forming and resorbing activity. Thus it would be beneficial to provide antagonists of osteoclast xcex1Vxcex23 which are effective inhibitors of bone resorption and therefore are useful in the treatment or prevention of osteoporosis.
The role of the xcex1Vxcex23 integrin in smooth muscle cell migration also makes it a therapeutic target for prevention or inhibition of neointimal hyperplasia which is a leading cause of restenosis after vascular procedures (Choi et al., J. Vasc. Surg. Vol. 19(1) (1994) 125-34). Prevention or inhibition of neointimal hyperplasia by pharmaceutical agents to prevent or inhibit restenosis would be beneficial.
White (Current Biology, Vol. 3(9)(1993) 596-599) has reported that adenovirus uses xcex1Vxcex23 for entering host cells. The integrin appears to be required for endocytosis of the virus particle and may be required for penetration of the viral genome into the host cell cytoplasm. Thus compounds which inhibit xcex1Vxcex23 would find usefulness as antiviral agents.
The compounds of this invention are 1) xcex1Vxcex23 integrin antagonists; or 2) xcex1Vxcex25 integrin antagonists; or 3) mixed or dual xcex1Vxcex23/xcex1Vxcex25 antagonists. The present invention includes compounds which inhibit the respective integrins and also includes pharmaceutical compositions comprising such compounds. The present invention further provides for methods for treating or preventing conditions mediated by the xcex1Vxcex23 and/or xcex1Vxcex25 receptors in a mammal in need of such treatment comprising administering a therapeutically effective amount of the compounds of the present invention and pharmaceutical compositions of the present invention. Administration of such compounds and compositions of the present invention inhibits angiogenesis, tumor metastasis, tumor growth, osteoporosis, Paget""s disease, humoral hypercalcemia of malignancy, retinopathy, macular degeneration, arthritis, periodontal disease, smooth muscle cell migration, including restenosis and artherosclerosis, and viral diseases.
The compounds of the present invention further show greater selectivity for the xcex1Vxcex23 and/or xcex1Vxcex25 integrin than for the xcex1Vxcex26 integrin. It has been found that the selective antagonism of the xcex1Vxcex23 integrin is desirable in that the xcex1Vxcex26 integrin may play a role in normal physiological processes of tissue repair and cellular turnover that routinely occur in the skin and pulmonary tissue, and the inhibition of this function can be deleterious. Therefore, compounds of the present invention which selectively inihibit the xcex1Vxcex23 integrin as opposed to the xcex1Vxcex26 integrin have reduced side-effects associated with inhibtion of the xcex1Vxcex26 integrin.
The present invention relates to a class of compounds represented by the Formula I. 
or a pharmaceutically acceptable salt thereof, wherein 
is a 4-8 membered monocyclic or a 7-12 membered bicyclic ring, optionally saturated or unsaturated, optionally substituted with one or more substituent selected from the group consisting of alkyl, haloalkyl, aryl, heteroaryl, halogen, alkoxyalkyl, aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl, thioalkyl, amino, alkylamino, arylamino, alkylsulfonamide, acyl, acylamino, alkylsulfone, sulfonamide, alkylsulfoxide, allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, carboxamide, cyano, and xe2x80x94(CH2)n COR wherein n is 0-2 and R is hydroxy, alkoxy, alkyl or amino;
A1 is a 5-9 membered monocyclic or 7-12 membered bicyclic heterocycle of the formula 
xe2x80x83containing at least one nitrogen atom and optionally 1 to 3 additional heteroatoms, selected from the group consisting of O, N, S, CO, or SO2 optionally saturated or unsaturated; optionally substituted by one or more Rk selected from the group consisting of hydroxy, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, thioalkyl, cyano, amino, alkylamino, halogen, acylamino, sulfonamide and xe2x80x94COR wherein R is hydroxy, alkoxy, alkyl or amino; or
A1 is 
xe2x80x83wherein Y1 is selected from the group consisting of Nxe2x80x94R2, O, and S;
R2 is selected from the group consisting of H; alkyl; cycloalkyl; aryl; hydroxy; alkoxy; cyano; alkenyl; alkynyl; amido; alkylcarbonyl; arylcarbonyl; alkoxycarbonyl; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl;
R2 taken together with R7 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, thioalkyl, alkylamino, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fused phenyl; or
R2 taken together with R7 forms a 4-12 membered heterocycle containing one or more heteroatom selected from O, N and S optionally unsaturated; or
R2 taken together with R7 forms a 5 membered heteroaromatic ring fused with an aryl or heteroaryl ring;
R7 (when not taken together with R2) and R8 are independently selected from the group consisting of H; alkyl; alkenyl; alkynyl; aralkyl; amino; alkylamino; hydroxy; alkoxy; arylamino; amido, alkylcarbonyl, arylcarbonyl; alkoxycarbonyl, aryloxy, aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl; cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl; or
NR7 and R8 taken together form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of O, N and S;
R5 is selected from the group consisting of H, hydroxy, alkoxy, cycloalkyl, and alkyl; or 
A1 is
wherein
Y2 is selected from the group consisting of alkyl; cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles;
Z1 is selected from the group consisting of CH2, O, CH2O, NRk, CO, S, SO, CH(OH) and SO2, wherein Rk is selected from H or lower alkyl;
Z2 is a 1-5 carbon linker optionally containing one or more heteroatom selected from the group consisting of O, S and N; alternatively Z1-Z2 may further contain a carboxamide, sulfone, sulfonamide, alkenyl, alkynyl, or acyl group;
wherein the carbon and nitrogen atoms of Z1-Z2 are optionally substituted by alkyl, cycloalkyl, alkoxy, thioalkyl, alkylsulfone, aryl, arylsulfone, alkoxyalkyl, hydroxy, alkylamino, heteroaryl, alkenyl, alkynyl, carboxyalkyl, halogen, haloalkyl or acylamino;
n is an integer 1 or 2;
Rc is selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, halogen, hydroxy, nitro, alkoxy, amino, haloalkyl, aryl, heteroaryl, alkoxyalkyl, aminoalkyl, hydroxyalkyl, thioalkyl, alkylamino, arylamino, alkylsulfonylamino, acyl, acylamino, sulfonyl, sulfonamide, allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, alkynylalkyl, carboxy, alkoxycarbonyl, carboxamido, cyano, and xe2x80x94(CH2)nCOR wherein n is 0-2 and R is selected from hydroxy, alkoxy, alkyl and amino;
X is selected from the group consisting of xe2x80x94CHRexe2x80x94, xe2x80x94NRfxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94, and xe2x80x94COxe2x80x94 wherein Re is H, lower alkyl, alkoxy, cycloalkyl, alkoxyalkyl, hydroxy, alkynyl, alkenyl, haloalkyl, thioalkyl or aryl; wherein when Re is hydroxy, the hydroxy group can optionally form a lactone with the carboxylic acid function of the chain; wherein Rf is selected from the group consisting of H, alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, arakylheteroaryl, and haloalkyl;
Y is selected from the group consisting of (CH2)p, xe2x80x94CRgxe2x80x94, xe2x80x94NRg, CO and SO2, wherein Rg is selected from the group consisting of H, alkyl, haloalkyl, alkoxyalkyl, alkynyl, aryl, heteroaryl, aralkyl, hydroxy, hydroxyalkyl, alkoxy, and carboxyalkyl; wherein p is 0 or 1;
optionally the group Xxe2x80x94Y can contain a moiety selected from the group consisting of acyl, alkyl, sulfonyl, amino, ether, thioether, carboxamido, sulfonamido, aminosulfonyl and olefins;
Y3 and Y4 are independently selected from the group consisting of alkyl, haloalkyl, hydroxy, alkoxy, cyano, halogen, aralkyl, heteroaralkyl, alkoxyalkyl, hydroxyalkyl, aryloxyalkyl, alkylsulfone, alkene or alkyne; wherein the alkyl group optionally contains one or more heteroatoms selected from the group consisting of N, O, and S;
alternately, when Y3 is an aryl or a heteroaryl, Y4 may be an aryl, heteroaryl, alkene, alkyne, alkoxy, hydroxy, cyano, alkoxyalkyl or an alkylsulfone;
Y5 is C;
Optionally, Y3, Y4 and Y5 may form a sulfone (SO2) group; or
Y3 taken together with Y4 forms a 3-8 membered monocyclic or a 7-11 membered bicyclic ring, optionally containing one or more double bonds, optionally containing one or more heteroatom or functional group selected from O, NRg, S, CO or SO2, optionally substituted with one or more substituent selected from the group consisting of alkyl, heteroalkyl, hydroxy, halogen, haloalkyl, alkoxy, alkyne, cyano, alkylsulfone, sulfonamide, aryl, heteroaryl, arakylaryl, heteroarakyl arylcarboalkoxy and carboxyalkyl;
Rb is X2xe2x80x94Rh wherein X2 is selected from the group consisting of O, S and NRj wherein Rh and Rj are independently selected from the group consisting of H, alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarakylaryl, acyl, and alkoxyalkyl;
It is another object of the invention to provide pharmaceutical compositions comprising compounds of the Formula I. Such compounds and compositions are useful in selectively inhibiting or antagonizing the xcex1Vxcex23 and/or xcex1Vxcex25 integrins and therefore in another embodiment the present invention relates to a method of selectively inhibiting or antagonizing the xcex1Vxcex23 and/or xcex1Vxcex25 integrin. The invention further involves treating or inhibiting pathological conditions associated therewith such as osteoporosis, humoral hypercalcemia of malignancy, Paget""s disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration and diabetic retinopathy, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cell migration and restenosis in a mammal in need of such treatment. Additionally, such pharmaceutical agents are useful as antiviral agents, and antimicrobials. The compounds of the present invention may be used alone or in combination with other pharmaceutical agents.
The present invention relates to a class of compounds represented by the Formula I, described above.
Wherein 
is is a 4-8 membered monocyclic or a 7-12 membered bicyclic ring, optionally saturated or unsaturated, optionally substituted with one or more substituent selected from the group consisting of lower alkyl, alkynyl, alkenyl, halogen, alkoxy, hydroxy, cyano, amino, alkylamino, dialkylamino or methylsulfonamide.
A1 is a 5-9 membered monocyclic or 7-12 membered bicyclic heterocycle of the formula 
which includes the following heterocyclic ring systems containing at least one nitrogen atom: 
wherein Za is H, alkyl, alkoxy, hydroxy, amine, alkylamine, dialkylamine, carboxyl, alkoxycarbonyl, hydroxyalkyl, halogen or haloalkyl and R1 is H, alkyl, alkoxyalkyl, acyl, haloalkyl or alkoxycarbonyl. More specifically some examples include pyridylamino, imidazolylamino, morpholinopyridine, tetrahydronaphthyridine, oxazolylamino, thiazolylamino, pyrimidinylamino, quinoline, tetrahydroquinoline, imidazopyridine, benzimidazole, pyridone or quinolone.
The following heteroaryls include the ring systems described above. 
For the pyridyl derived heterocycle, the substituents X4 and X5 are selected from the group consisting of H, alkyl, branched alkyl, alkylamino, alkoxyalkylamino, haloalkyl, thioalkyl, halogen, amino, alkoxy, aryloxy, alkoxyalkyl, hydroxy, cyano or acylamino groups.
In another embodiment of the invention, the substituents X4 and X5 can be methyl, methoxy, amine, methylamine, trifluoromethyl, dimethylamine, hydroxy, chloro, bromo, fluoro and cyano. X6 may preferentially be H, alkyl, hydroxy, halogen, alkoxy and haloalkyl. Alternately, the pyridyl ring can be fused with a 4-8 membered ring, optionally saturated or unsaturated. Some examples of these ring systems include tetrahydronaphthyridine, quinoline, tetrahydroquinoline, azaquinoline, morpholinopyridine, imidazopyridine and the like. The monocyclic ring systems such as imidazole, thiazole, oxazole, pyrazole, and the like, may contain an amino or alkylamino substituent at any position within the ring.
In another embodiment of the present invention, when Z1 of Formula I is CO or SO2, the linkage A1xe2x80x94Z2 of Formula I includes the heterocycle derived ring systems such as: pyridine, imidazole, thiazole, oxazole, benzimidazole, imidazopyridine and the like.
Other heterocycles for A1xe2x80x94Z2 of the present invention include 
wherein
X4 is as defined above.
Y3 and Y4 are as defined above; or
Y3 taken together with Y4 forms a 3-8 membered monocyclic or a 7-11 membered bicyclic ring, optionally containing one or more double bonds, optionally containing one or more heteroatoms or functional groups selected from O, NRg, S, CO or SO2, optionally substituted with one or more substituent selected from the group consisting of alkyl, haloalkyl, halogen, haloalkyl, alkoxy, alkyne, cyano, alkylsulfone, sulfonamide, carboalkoxy and carboxyalkyl; wherein Rg is selected from the group consisting of H, alkyl, haloalkyl, alkoxyalkyl, aryl, heteroaryl, aralkyl, and carboxyalkyl.
The invention further relates to pharmaceutical compositions containing therapeutically effective amounts of the compounds of Formula 1.
The invention also relates to a method of selectively inhibiting or antagonizing the xcex1Vxcex23 integrin and/or the xcex1Vxcex25 integrin and more specifically relates to a method of inhibiting bone resorption, periodontal disease, osteoporosis, humoral hypercalcemia of malignancy, Paget""s disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration and diabetic retinopathy, arthritis, including rheumatoid arthritis, smooth muscle cell migration and restenosis by administering a therapeutically effective amount of a compound of the Formula I to achieve such inhibition together with a pharmaceutically acceptable carrier.
The following is a list of definitions of various terms used herein:
As used herein, the terms xe2x80x9calkylxe2x80x9d or xe2x80x9clower alkylxe2x80x9d refer to a straight chain or branched chain hydrocarbon radicals having from about 1 to about 10 carbon atoms, and more preferably 1 to about 6 carbon atoms. Examples of such alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl, and the like.
As used herein the terms xe2x80x9calkenylxe2x80x9d or xe2x80x9clower alkenylxe2x80x9d refer to unsaturated acyclic hydrocarbon radicals containing at least one double bond and 2 to about 6 carbon atoms, which carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety, relative to groups substituted on the double bond carbons. Examples of such groups are ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and the like.
As used herein the terms xe2x80x9calkynylxe2x80x9d or xe2x80x9clower alkynylxe2x80x9d refer to acyclic hydrocarbon radicals containing one or more triple bonds and 2 to about 6 carbon atoms. Examples of such groups are ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein means saturated or partially unsaturated cyclic carbon radicals containing 3 to about 8 carbon atoms and more preferably 4 to about 6 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cy clopropenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-1-yl, and the like.
The term xe2x80x9carylxe2x80x9d as used herein denotes aromatic ring systems composed of one or more aromatic rings. Preferred aryl groups are those consisting of one, two or three aromatic rings. The term embraces aromatic radicals such as phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl and the like.
As used herein, the term xe2x80x9ccyanoxe2x80x9d is represented by a radical of the formula 1 
The terms xe2x80x9chydroxyxe2x80x9d and xe2x80x9chydroxylxe2x80x9d as used herein are synonymous and are represented by a radical of the formula 2 
The term xe2x80x9clower alkylenexe2x80x9d or xe2x80x9calkylenexe2x80x9d as used herein refers to divalent linear or branched saturated hydrocarbon radicals of 1 to about 6 carbon atoms.
As used herein the term xe2x80x9calkoxyxe2x80x9d refers to straight or branched chain oxy containing radicals of the formula xe2x80x94OR20, wherein R20 is an alkyl group as defined above. Examples of alkoxy groups encompassed include methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy, sec-butoxy, t-butoxy and the like.
As used herein the terms xe2x80x9carylalkylxe2x80x9d or xe2x80x9caralkylxe2x80x9d refer to a radical of the formula 
3 wherein R21 is aryl as defined above and R22 is an alkylene as defined above. Examples of aralkyl groups include benzyl, pyridylmethyl, naphthylpropyl, phenethyl and the like.
As used herein the term xe2x80x9cnitroxe2x80x9d is represented by a radical of the formula 4 
As used herein the term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to bromo, chloro, fluoro or iodo.
As used herein the term xe2x80x9chaloalkylxe2x80x9d refers to alkyl groups as defined above substituted with one or more of the same or different halo groups at one or more carbon atom. Examples of haloalkyl groups include trifluoromethyl, dichloroethyl, fluoropropyl and the like.
As used herein the term xe2x80x9ccarboxylxe2x80x9d or xe2x80x9ccarboxyxe2x80x9d refers to a radical of the formula xe2x80x94COOH.
As used herein the term xe2x80x9ccarboxyl esterxe2x80x9d refers to a radical of the formula xe2x80x94COOR23 wherein R23 is selected from the group consisting of H, alkyl, heteroalkyl, heteroaryl, heteroaralkylalkyl, aralkyl or aryl as defined above.
As used herein the term xe2x80x9ccarboxyl derivativexe2x80x9d refers to a radical of the formula 
5 wherein Y6 and Y7 are independently selected from the group consisting of O, N or S and R23 is selected from the group consisting of H, alkyl, aralkyl, heteroalkyl, heteroaryl, heteroaralkylalkyl or aryl as defined above.
As used herein the term xe2x80x9caminoxe2x80x9d is represented by a radical of the formula xe2x80x94NH2.
As used herein the term xe2x80x9calkylsulfonylxe2x80x9d or xe2x80x9calkylsulfonexe2x80x9d refers to a 
radical of the formula 6 wherein R24 is alkyl, cycloalkyl, heteroalkyl or heterocycloalkyl as defined above.
As used herein the term xe2x80x9calkylthioxe2x80x9d refers to a radical of the formula xe2x80x94SR24 wherein R24 is alkyl or heteroalkyl as defined above.
As used herein the term xe2x80x9csulfonic acidxe2x80x9d refers to a radical of the 
formula 7 wherein R25 is alkyl, cycloalkyl, heteroalkyl, hetero-cycloalkyl as defined above.
As used herein the term xe2x80x9csulfonamidexe2x80x9d or xe2x80x9csulfonamidoxe2x80x9d refers to a radical of the formula 
8 wherein R7 and R8 are as defined above.
As used herein the term xe2x80x9cfused arylxe2x80x9d refers to an aromatic ring such as the aryl groups defined above fused to one or more phenyl rings.
Embraced by the term xe2x80x9cfused arylxe2x80x9d is the radical naphthyl and the like.
As used herein the terms xe2x80x9cmonocyclic heterocyclexe2x80x9d or xe2x80x9cmonocyclic heterocyclicxe2x80x9d refer to a monocyclic ring containing from 4 to about 12 atoms, and more preferably from 5 to about 10 atoms, wherein 1 to 3 of the atoms are heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur with the understanding that if two or more different heteroatoms are present at least one of the heteroatoms must be nitrogen. Representative of such monocyclic heterocycles are imidazole, furan, pyridine, oxazole, pyran, triazole, thiophene, pyrazole, thiazole, thiadiazole, and the like.
As used herein the term xe2x80x9cfused monocyclic heterocyclexe2x80x9d refers to a monocyclic heterocycle as defined above with a benzene fused thereto. Examples of such fused monocyclic heterocycles include benzofuran, benzopyran, benzodioxole, benzothiazole, benzothiophene, benzimidazole and the like.
As used herein the term xe2x80x9cmethylenedioxyxe2x80x9d refers to the radical 
and the term xe2x80x9cethylenedioxyxe2x80x9d refers to the radical 
of the formula 9 and 10. As used herein the term xe2x80x9c4-12 membered dinitrogen containing heterocycle refers to a radical of the formula 
11 wherein m is 1-4 and R19 is H, alkyl, aryl, heteroalkyl, heteroaryl, heteroaralkyl, alkyl or aralkyl and more preferably refers to 4-9 membered ring and includes rings such as imidazoline.
As used herein the term xe2x80x9c5-membered optionally substituted heteroaromatic ringxe2x80x9d includes for example a radical of the formula 
and xe2x80x9c5-membered heteroaromatic ring fused with a phenylxe2x80x9d refers to such a xe2x80x9c5-membered heteroaromatic ringxe2x80x9d with a phenyl fused thereto. Representative of such 5-membered heteroaromatic rings fused with a phenyl is benzimidazole.
As used herein the term xe2x80x9cbicycloalkylxe2x80x9d refers to a bicyclic hydrocarbon radical containing 6 to about 12 carbon atoms which is saturated or partially unsaturated.
As used herein the term xe2x80x9cacylxe2x80x9d refers to a radical of the formula 
12 wherein R26 is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, hetero alkyl, heterocycloalkyl, or aralkyl and optionally substituted thereon as defined above. Encompassed by such radical are the groups acetyl, benzoyl and the like.
As used herein the term xe2x80x9cthioxe2x80x9d refers to a radical of the formula 
As used herein the term xe2x80x9csulfonylxe2x80x9d refers to a radical of the formula 
14 wherein R27 is alkyl, aryl, heteroalkyl, heteroaryl, heteroaralkylalkyl or aralkyl as defined above.
As used herein the term xe2x80x9chaloalkylthioxe2x80x9d refers to a radical of the formula xe2x80x94Sxe2x80x94R28 wherein R28 is haloalkyl as defined above.
As used herein the term xe2x80x9caryloxyxe2x80x9d refers to a radical of the formula 
15 wherein R29 is aryl or heteroaryl as defined above.
As used herein the term xe2x80x9cacylaminoxe2x80x9d refers to a radical of the formula 
wherein R30 is alkyl, heteroalkyl, heteroaryl, heteroaralkylalkyl, aralkyl or aryl as defined above.
As used herein the term xe2x80x9camidoxe2x80x9d refers to a radical of the formula 
As used herein the term xe2x80x9calkylaminoxe2x80x9d refers to a radical of the formula xe2x80x94NHR32 wherein R32 is alkyl or heteroalkyl as defined above.
As used herein the term xe2x80x9cdialkylaminoxe2x80x9d refers to a radical of the formula xe2x80x94NR33R34 wherein R33 and R34 are the same or different alkyl or cycloalkyl groups as defined above.
As used herein the term xe2x80x9ctrifluoromethylxe2x80x9d refers to a radical of the formula 
17
As used herein the term xe2x80x9ctrifluoroalkoxyxe2x80x9d refers to a radical of the formula 
18 wherein R35 is a bond or an alkylene as defined above.
As used herein the term xe2x80x9calkylaminosulfonylxe2x80x9d or xe2x80x9caminosulfonylxe2x80x9d refers to a radical of the formula 19 
wherein is R36 is alkyl, heteroalkyl, heteroaralkylalkyl, or heteroaryl as defined above.
As used herein the term xe2x80x9calkylsulfonylaminoxe2x80x9d or xe2x80x9calkylsulfonamidexe2x80x9d refers to a radical of the formula 20 
wherein R36 is alkyl, heteroalkyl, heterocycloalkyl, or cycloalkyl as defined above.
As used herein the term xe2x80x9ctrifluoromethylthioxe2x80x9d refers to a radical of the formula 
21
As used herein the term xe2x80x9ctrifluoromethylsulfonylxe2x80x9d refers to a radical of the formula 
22.
As used herein the term xe2x80x9c4-12 membered mono-nitrogen containing monocyclic or bicyclic ringxe2x80x9d refers to a saturated or partially unsaturated monocyclic or bicyclic ring of 4-12 atoms and more preferably a mono or bicyclic ring of 4-9 atoms wherein one atom is nitrogen. Such rings may optionally contain additional heteroatoms selected from nitrogen, oxygen or sulfur. Included within this group are morpholine, piperidine, piperazine, thiomorpholine, pyrrolidine, proline, azacycloheptene and the like.
As used herein the term xe2x80x9cbenzylxe2x80x9d refers to the radical 
As used herein the term xe2x80x9cphenethylxe2x80x9d refers to the radical 
As used herein the term xe2x80x9c4-12 membered mono-nitrogen containing monosulfur or monooxygen containing heterocyclic ringxe2x80x9d refers to a ring consisting of 4 to 12 atoms and more preferably 4 to 9 atoms wherein at least one atom is a nitrogen and at least one atom is oxygen or sulfur. Encompassed within this definition are rings such as thiazoline and the like.
As used herein the term xe2x80x9carylsulfonylxe2x80x9d or xe2x80x9carylsulfonexe2x80x9d refers to a radical of the formula 25 
wherein R37 is aryl as defined above.
As used herein the terms xe2x80x9calkylsulfoxidexe2x80x9d or xe2x80x9carylsulfoxidexe2x80x9d refer to radicals of the formula 
26 wherein R38 is, respectively, alkyl, heteroalkyl, heteroaryl or aryl as defined above.
As used herein the term xe2x80x9carylthioxe2x80x9d refers to a radical of the formula 27 
wherein R42 is aryl as defined above.
As used herein the term xe2x80x9cmonocyclic heterocycle thioxe2x80x9d refers to a radical of the formula 
28 wherein R43 is a monocyclic heterocycle radical as defined above.
As used herein the terms xe2x80x9cmonocyclic heterocycle sulfoxidexe2x80x9d and xe2x80x9cmonocyclic heterocycle sulfonexe2x80x9d refer, respectively, to radicals of the formula 29 30 
wherein R43 is a monocyclic heterocycle radical as defined above.
As used herein the term xe2x80x9calkylcarbonylxe2x80x9d refers to a radical of the formula 
31 wherein R50 is alkyl, heteroaryl, heterocycloaryl or cycloalkyl as defined above.
As used herein the term xe2x80x9carylcarbonylxe2x80x9d refers to a radical of the formula 
32 wherein R51 is aryl as defined above.
As used herein the term xe2x80x9calkoxycarbonylxe2x80x9d refers to a radical of the formula 
33 wherein R52 is alkoxy as defined above.
As used herein the term xe2x80x9caryloxycarbonylxe2x80x9d refers to a radical of the formula 
34 wherein R51 is aryl as defined above.
As used herein the term xe2x80x9chaloalkylcarbonylxe2x80x9d refers to a radical of the formula 
35 wherein R53 is haloalkyl as defined above.
As used herein the term xe2x80x9chaloalkoxycarbonylxe2x80x9d refers to a radical of the formula 
36 wherein R53 is haloalkyl as defined above.
As used herein the term xe2x80x9calkylthiocarbonylxe2x80x9d refers to a radical of the formula 
37 wherein R50 is alkyl or cycloalkyl as defined above.
As used herein the term xe2x80x9carylthiocarbonylxe2x80x9d refers to a radical of the formula 
38 wherein R51 is aryl as defined above.
As used herein the term xe2x80x9cacyloxymethoxycarbonylxe2x80x9d refers to a radical of the formula 
39 wherein R54 is acyl as defined above.
As used herein the term xe2x80x9carylaminoxe2x80x9d refers to a radical of the formula R51xe2x80x94NHxe2x80x94 wherein R51 is aryl as defined above.
As used herein the term xe2x80x9cacyloxyxe2x80x9d refers to a radical of the formula R55xe2x80x94Oxe2x80x94 wherein R55 is acyl as defined above.
As used herein the term xe2x80x9calkenylalkylxe2x80x9d refers to a radical of the formula R50xe2x80x94R57xe2x80x94 wherein R50 is an alkenyl as defined above and R57 is alkylene as defined above.
As used herein the term xe2x80x9calkenylenexe2x80x9d refers to a linear hydrocarbon radical of 1 to about 8 carbon atoms containing at least one double bond.
As used herein the term xe2x80x9calkoxyalkylxe2x80x9d refers to a radical of the formula R56xe2x80x94R57xe2x80x94 wherein R56 is alkoxy as defined above and R57 is alkylene as defined above.
As used herein the term xe2x80x9calkynylalkylxe2x80x9d refers to a radical of the formula R59xe2x80x94R60xe2x80x94 wherein R59 is alkynyl as defined as above and R60 is alkylene as defined as above.
As used herein the term xe2x80x9calkynylenexe2x80x9d refers to divalent alkynyl radicals of 1 to about 6 carbon atoms.
As used herein the term xe2x80x9callylxe2x80x9d refers of a radical of the formula xe2x80x94CH2CHxe2x95x90CH2.
As used herein the term xe2x80x9caminoalkylxe2x80x9d refers to a radical of the formula H2Nxe2x80x94R61 wherein R61 is alkylene as defined above.
As used herein the term xe2x80x9cbenzoylxe2x80x9d refers to the aryl radical C6H5xe2x80x94COxe2x80x94.
As used herein the term xe2x80x9ccarboxamidexe2x80x9d or xe2x80x9ccarboxamidoxe2x80x9d refer to a radical of the formula xe2x80x94COxe2x80x94NH2.
As used herein the term xe2x80x9ccarboxyalkylxe2x80x9d refers to a radical HOOCxe2x80x94R62xe2x80x94 wherein R62 is alkylene as defined as above.
As used herein the term xe2x80x9ccarboxylic acidxe2x80x9d refers to the radical xe2x80x94COOH.
As used herein the term xe2x80x9cetherxe2x80x9d refers to a radical of the formula R63xe2x80x94Oxe2x80x94 wherein R63 is selected from the group consisting of alkyl, aryl and heteroaryl.
As used herein the term xe2x80x9chaloalkylsulfonylxe2x80x9d refers to a radical of the formula 
wherein the R64 is haloalkyl as defined above.
As used herein the term xe2x80x9cheteroarylxe2x80x9d refers to an aryl radical contain at least one heteroatom.
As used herein the term xe2x80x9chydroxyalkylxe2x80x9d refers to a radical of the formula HOxe2x80x94R65 wherein R65 is alkylene as defined above.
As used herein the term xe2x80x9cketoxe2x80x9d refers to a carbonyl group joined to 2 carbon atoms.
As used herein the term xe2x80x9clactonexe2x80x9d refers to an anhydro cyclic ester produced by intramolecular condensation of a hydroxy acid with the elimination of water.
As used herein the term xe2x80x9colefinxe2x80x9d refers to an unsaturated hydrocarbon radical of the type CnH2n.
As used herein the term xe2x80x9csulfonexe2x80x9d refers to a radical of the formula R66xe2x80x94SO2xe2x80x94 wherein R66 is alkyl or cycloalkyl as defined above.
As used herein the term xe2x80x9cthioalkylxe2x80x9d refers to a radical of the formula R77xe2x80x94Sxe2x80x94 wherein R77 is alkyl as defined above.
As used herein the term xe2x80x9cthioetherxe2x80x9d refers to a radical of the formula R78xe2x80x94Sxe2x80x94 wherein R78 is alkyl, aryl or heteroaryl.
As used herein the term xe2x80x9ctrifluoroalkylxe2x80x9d refers to an alkyl radical as defined above substituted with three halo radicals as defined above.
The term xe2x80x9ccompositionxe2x80x9d as used herein means a product which results from the mixing or combining of more than one element or ingredient.
The term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d, as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a chemical agent.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
The following is a list of abbreviations and the corresponding meanings as used interchangeably herein:
1H-NMR=proton nuclear magnetic resonance
AcOH=acetic acid
Ar=Argon
BOC=tert-butoxycarbonyl
BuLi=butyl lithium
Cat.=catalytic amount
CH2Cl2=dichloromethane
CH3CN=acetonitrile
CH3I=iodomethane
CHN analysis=carbon/hydrogen/nitrogen elemental analysis
CHNCl analysis=carbon/hydrogen/nitrogen/chlorine elemental analysis
CHNS analysis=carbon/hydrogen/nitrogen/sulfur elemental analysis
DEAD=diethylazodicarboxylate
DIAD=diisopropylazodicarboxylate
DI water=deionized water
DMA=N,N-dimethylacetamide
DMAC=N,N-dimethylacetamide
DMF=N,N-dimethylformamide
EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Et=ethyl
EtI=ethyl iodide
Et2O=diethyl ether
Et3N=triethylamine
EtOAc=ethyl acetate
EtOH=ethanol
FAB MS=fast atom bombardment mass spectroscopy
g=gram(s)
HCl=hydrochloric acid
HOBT=1-hydroxybenzotriazole hydrate
hplc=high performance liquid chromatography
HPLC=high performance liquid chromatography
IPA=isopropyl alcohol
i-Pr=iso propyl
i-Prop=iso propyl
K2CO3=potassium carbonate
KF=potassium fluoride
kg=kilogram
KHxe2x80x94potassium hydride
KMnO4=potassium permanganate
KOH=potassium hydroxide
KSCN=potassium thiocyanate
L=Liter
LDA=Lithium Diisopropylamide
LiOH=lithium hydroxide
LTMP=Lithium tetramethylpiperidide
Me=methyl
MeOH=methanol
mg=milligram
MgSO4=magnesium sulfate
ml=milliliter
mL=milliliter
MS=mass spectroscopy
NaHxe2x80x94sodium hydride
NaHCO3=sodium bicarbonate
NaOH=sodium hydroxide
NaOMe=sodium methoxide
NH4+HCO2xe2x88x92=ammonium formate
NH4OH=ammonium hydroxide
NMR=nuclear magnetic resonance
Pd=palladium
Pd/C=palladium on carbon
Ph=phenyl
psi=pressure per square inch
Pt=platinum
Pt/C=platinum on carbon
RP HPLC=reverse phase high performance liquid chromatography
RT=room temperature
t-BOC=tert-butoxycarbonyl
TEA=triethylamine
TFA=trifluoroacetic acid
THF=tetrahydrofuran
TLCxe2x80x94thin layer chromatography
TMS=trimethylsilyl
xcex94=heating the reaction mixture
The compounds as shown above can exist in various isomeric forms and all such isomeric forms are meant to be included. Tautomeric forms are also included as well as pharmaceutically acceptable salts of such isomers and tautomers.
In the structures and formulas herein, a bond drawn across a bond of a ring can be to any available atom on the ring. a ring can be to any available atom on the ring.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to a salt prepared by contacting a compound of Formula I with an acid whose anion is generally considered suitable for human consumption. Examples of pharmacologically acceptable salts include the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, propionate, lactate, maleate, malate, succinate, tartrate salts and the like. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; or alkaline earth metal salts. All of the pharmacologically acceptable salts may be prepared by conventional means. (See Berge et al., J Pharm. Sci, 66(1), 1-19 (1977) for additional examples of pharmaceutically acceptable salts.)
The present invention includes within its scope prodrugs of compounds of Formula I. These prodrugs are typically derivatives of the compounds of Formula I which are convertible to the active compounds on in-vivo exposure. These compounds may be derivatives of carboxylic acid (such as ester, amide, orthoester, urea and the like). Similarly derivatives of amine, hydroxy or other functional groups may be used as handles for prodrug formation. Thus in the present invention, administering a compound for treatment of various conditions would include compounds specifically disclosed or the compounds which may not be specifically disclosed but would be converted to the specifically disclosed compound of Formula 1 on in-vivo administration. The methods described in literature (e.g., Design of pro-drugs, H. Bundgaard, Elsevier, 1985; Annual reports in Medicinal Chemistry, Vol 10, R. V. Heinzelman, ed.: Academic Press, 306-326, 1975) may be used for the preparation of prodrugs.
The compounds of the present invention may be chiral or achiral. These compounds may exist as racemic mixtures, diastereomers or pure enantiomers. For a chiral compound of present invention, separate enantiomers or all mixtures of diastereomers are included.
For the selective inhibition or antagonism of xcex1Vxcex23 and/or xcex1vxcex25 integrins, compounds of the present invention may be administered orally, parenterally, or by inhalation spray, or topically in unit dosage formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes, for example, subcutaneous, intravenous, intramuscular, intrasternal, transmuscular infusion techniques or intraperitonally.
The compounds of the present invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds required to prevent or arrest the progress of or to treat the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
Accordingly, the present invention provides a method of treating conditions mediated by selectively inhibiting or antagonizing the xcex1Vxcex23 and/or xcex1Vxcex25 cell surface receptor which method comprises administering a therapeutically effective amount of a compound selected from the class of compounds depicted in the above formulas, wherein one or more compound is administered in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as xe2x80x9ccarrierxe2x80x9d materials) and if desired other active ingredients. More specifically, the present invention provides a method for inhibition of the xcex1Vxcex23 and/or xcex1Vxcex25 cell surface receptors. Most preferably the present invention provides a method for inhibiting bone resorption, treating osteoporosis, inhibiting humoral hypercalcemia of malignancy, treating Paget""s disease, inhibiting tumor metastasis, inhibiting neoplasia (solid tumor growth), inhibiting angiogenesis including tumor angiogenesis, treating retinopathy including macular degeneration and diabetic retinopathy, inhibiting arthritis, psoriasis and periodontal disease, and inhibiting smooth muscle cell migration including restenosis.
Based upon standard laboratory experimental techniques and procedures well known and appreciated by those skilled in the art, as well as comparisons with compounds of known usefulness, the compounds of Formula I can be used in the treatment of patients suffering from the above pathological conditions. One skilled in the art will recognize that selection of the most appropriate compound of the invention is within the ability of one with ordinary skill in the art and will depend on a variety of factors including assessment of results obtained in standard assay and animal models.
Treatment of a patient afflicted with one of the pathological conditions comprises administering to such a patient an amount of compound of the Formula I which is therapeutically effective in controlling the condition or in prolonging the survivability of the patient beyond that expected in the absence of such treatment. As used herein, the term xe2x80x9cinhibitionxe2x80x9d of the condition refers to slowing, interrupting, arresting or stopping the condition and does not necessarily indicate a total elimination of the condition. It is believed that prolonging the survivability of a patient, beyond being a significant advantageous effect in and of itself, also indicates that the condition is beneficially controlled to some extent.
As stated previously, the compounds of the invention can be used in a variety of biological, prophylactic or therapeutic areas. It is contemplated that these compounds are useful in prevention or treatment of any disease state or condition wherein the xcex1Vxcex23 and/or xcex1Vxcex25 integrin plays a role.
The dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions.
Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to 1.0 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 200 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regiment.
For administration to a mammal in need of such treatment, the compounds in a therapeutically effective amount are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and tableted or encapsulated for convenient administration. Alternatively, the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
The pharmaceutical compositions useful in the present invention may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.
In another embodiment, the present invention provides treatment or prevention of a neoplasia disease in a mammal by combining one or more xcex1vxcex23 integrin antagonists of the present invention with one or more chemotherapeutic agents. Among chemotherapeutic agents that may be used in combination with the xcex1vxcex23 antagonist compounds include but are not limited to 5-fluorouacil, cyclophosphamide, cisplatin, taxol, and doxorubicin are preferred. Other chemotherapeutics useful in combination and within the scope of the present invention include but are not limited to buserelin, topoisomerase inhibitors such as topotecan and irinotecan, mitoxantrone, BCNU, CPT-11, chlorotranisene, chromic phosphate, gemcitabine, dexamethasone, estradiol, estradiol valerate, estrogens conjugated and esterified, estrone, ethinyl estradiol, floxuridine, goserelin, hydroxyurea, carboplatin, melphalan, methotrexate, mitomycin and prednisone.
The methods and combinations using one provide treatment or prevention of a neoplasia disease in a mammal using one or more xcex1vxcex23 integrin antagonists described above with one or more chemotherapeutic agents described above. The method comprises treating a mammal with a therapeutically effective amount of an xcex1vxcex23 integrin antagonist in combination with a chemotherapeutic agent.
There are five major classes of chemotherapeutic agents currently in use for the treatment of cancer: natural products and their derivatives; anthracyclins; alkylating agents; antimetabolites; and hormonal agents. Chemotherapeutic agents are often referred to as antineoplastic agents. The alkylating agents are believed to act by alkylating and cross-linking guanine and possibly other bases.
In DNA, arresting cell division. Typical alkylating agents include nitrogen mustards, ethyleneimine compounds, alkyl sulfates, cislatin, and various nitrosoureas. A disadvantage with these compounds is that they not only attack malignant cells, but also other cells which are naturally dividing, such as those of bone marrow, skin, gastro-intestinal mucosa and fetal tissue.
Antimetaloties are typically reversible or irreversible enzyme inhibitors, or compounds that otherwise interfere with the replication, translation or transcription of nucleic acids. Several synthetic nucleosides have been identified that exhibit anticancer activity. A well-known nucleoside derivative with strong anticancer activity is 5-fluorouacil. 5-fluorouacil has been used clinically in the treatment of malignant tumors, including, for example, carcinomas, sarcomas, skin cancer, cancer of the digestive organs, and breast cancer. 5-fluoroucil, however, causes serious adverse reactions such as nausea, alopecia, stomatites, leukocytic thrombocytopenia, anorexia, pigmentation and edema.
Cytosine arabinoside (also referred to as Cytarabin, araC, and Cytosar) is a nucleoside analog of deoxycytidine that was first synthesized in 1950 and introduced into clinical medicine in 1963. It is currently an important drug in the treatment of acute myeloid leukemia. It is also active against acute lymphocytic leukemia, and to a lesser extent, is useful in chronic myelocytic leukemia and non-Hodgkin""s lymphoma.
The following table (Table 1) provides illustrative examples of median dosages for selected cancer agents that may be used in combination with a xcex1vxcex23 integrin antagonist agent. It should be noted that the specific dose regimen for the chemotherapeutic agents below will depend upon dosing considerations based upon a variety of factors including the type of neoplasia; the state of the neoplasm, the age, weight, sex and medical condition of the patient; the route of administration, the renal and hepatic function of the patient; and the particular combination employed.
The pharmaceutical compositions useful in the present invention may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.
The general synthetic sequences for preparing the compounds useful in the present invention are outlined in SCHEMES 1-3. Both an explanation of, and the actual procedures for, the various aspects of the present invention are described where appropriate. The following Schemes and Examples are intended to be merely illustrative of the present invention, and not limiting thereof in either scope or spirit. Those with skill in the art will readily understand that known variations of the conditions and processes described in the Schemes and Examples can be used to synthesize the compounds of the present invention.
Unless otherwise indicated all starting materials and equipment employed were commercially available. 
The compounds of formula A17 are generally prepared by reacting an intermediate of formula A16 with a compound of the formula A15. For example, when Z3 is a OH, SH or NHR group, A16 may be alkylated with A15 (Z4=Br or OMs) using a base such as sodium hydride, potassium hydride and preferably in a solvent such as dimethylsulfoxide or DMF. These reactions may preferentially be carried at 0xc2x0 C. to approximately 40xc2x0 C. Alternately, when Z3 and Z4 are both OH, the ether formation to product A17 may be accomplished by using Mitsunobu reaction. This reaction may preferentially be carried out using triarylphosphine (such as triphenylphoshine) and azodicarboxylate (such as diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, di-iso-propyl azodicarboxylate) in solvents such as DMF, methylene chloride, THF and the like. When Z3 carries a carboxylic acid or a sulfonic acid and Z4 is an amine, the standard coupling conditions may be used to synthesize the carboxamide (CONH) or the sulfonamide (SO2NH) containing targets A17.
Alternately, the compounds of formula A17 may be prepared by starting with compounds of general formula A18. For example, when Z5 in A18 is NH2, cyclic or acyclic guanidino containing compounds of formula A17 may be synthesized by adopting the methodologies discussed in e.g. U.S. Pat. Nos. 5,852,210 or 5,773,646. Similarly, compounds of formula A18 (Z5=NH2) may be treated with appropriately substituted heteroaromatic system (such as 2-fluoropyridine or 2-chloropyridine N-oxide) to give the target compounds A17. This reaction may preferentially be carried out by refluxing the intermediate A18 and 2-halopyridine N-oxide (such as 2-chloropyridine N-oxide) in solvents such as tert-butyl alcohol, tert-amyl alcohol in the presence of a base (such as sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate).
Compounds of the general formula A15, A16, A18 may be prepared by methodologies discussed hereinafter. 
Compounds of the formula A4 containing a methyl substituent may be prepared by starting with substituted propiophenone A1. Generation of enolate with a base (such as HMDS, LDA, NaH, KH) at low temperature (xe2x88x9278xc2x0-0xc2x0 C.) followed by quenching with an electrophile such as ethyl bromoacetate gives the intermediates A2. Base hydrolysis of the ester (using e.g; 1N NaOH) followed by repetition of the enolate chemistry using excess of a base (such as HMDS, LDA, NaH, KH) followed by reaction with electrophile (such as alkyl iodide, or benzyl halide) gives the intermediate A3. Esterification of the resulting acid with an alcohol in the presence of drops of acid gives the desired ester intermediate A3. Deoxygenation of carbonyl group gives the intermediate A4. This transformation may be carried out using catalytic hydrogenation conditions in the presence of an acid (such as phosphoric acid). Palladium on carbon and hydrogen under 5-60 psi can be used to achieve this reduction . The intermediates A3 and A4 are processed to the target compounds of Formula I by synthetic transformations outlined in Scheme 1. 
The compounds of Formula I, wherein A is substituted pyridyl may be prepared by adopting the general synthetic Scheme 3. For example, reaction of substituted 2-halopyridine N-oxide (such as A19a-A19d) with e.g. 3-aminopropanol gives the intermediates A20a-A20d. This reaction may preferentially be carried out by refluxing the intermediate 2-halopyridine N-oxide (such as 2-chloropyridine N-oxide) in solvents such as tert-butyl alcohol, tert-amyl alcohol in the presence of base (such as sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate). The preparative conditions described in WO 99/15508 (PCT US 98/19466) may be used for this transformation. Coupling of the intermediates A20a-A20d with A16 using Mitsunobu reaction gives the compounds containing the ether link. This reaction may preferentially be carried out using triarylphosphine (such as triphenylphoshine) and dialkyl azodicarboxylate (such as diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, di-iso-propyl azodicarboxylate) in solvents such as DMF, methylene chloride, or THF. N-Deoxygenation of the resulting intermediates followed by hydrolysis of the ester gives the target compounds (A21a-A21d). Reduction of the N-oxide bond may be accomplished using e.g., transfer hydrogenation (cyclohexene/Pd on carbon) or ammonium formate and Pd on carbon or iron powder and acetic acid. The nitro group in 21d may be hydrogenated using Pd on carbon or Pt on carbon as catalysts. This transformation may be carried out using solvents such as methanol, ethanol or THF. The hydrolysis of the ester group may be carried out using aqueous base (such as sodium hydroxide, lithium hydroxide or potassium hydroxide) in solvents such as methanol, ethanol and THF. 
A mixture of 2-chloropyridine-N-oxide (16.6 g, 100 mmole), 3-amino-1-butanol (15.3 ml, 200 mmole), NaHCO3 (42 g, 0.5 mole), and tert-amyl alcohol (100 ml) was heated to reflux. After 23 hours, the reaction was cooled, diluted with CH2Cl2 (300 ml), and filtered to remove insoluble materials. The filtrate was concentrated to afford a brown oil. The oil was dried under vacuum overnight. The ether (100 ml) was added to give a brown solid. The ether was decanted and the solid was washed further with ether/acetonitrile (3/1). The resulting solid was heated at 67xc2x0 C. under vacuum to give the desired product (13.5 g). 1H NMR was consistent with the proposed structure.